Depressive symptoms significantly increase the risk of acute coronary syndromes recurrence (ACS). Platelet-thrombus formation over a disrupted atherosclerotic plaque is fundamental for ACS recurrence.Serotonin (5-HT) is an important stimulant of platelet reactivity. Increased 5-HT-mediated platelet reactivity due to upregulation of the platelet 5-HT2A receptor, increases thrombosis formation and has been postulated to a major mechanism linking depression to ACS recurrence. It is not known at this time if depression interventions reverse the increased risk of ACS events in depressed patients. The selective serotonin reuptake inhibitors (SSRIs) and the 5-HT2A receptor antidepressants improve depressive symptoms at equal rates. Both types of antidepressants may attenuate platelet reactivity by improving depressive symptoms (CNS mediated indirect effects). However, the SSRIs and the 5-HT2A receptor antagonists may have additional but divergent pharmacologic effects on platelet reactivity (direct platelet effects). Given the relationship between depression, platelet-thrombus formation, and the ACS, those antidepressants capable not only of improving depression symptoms but also of inhibiting platelet reactivity directly, may have the greatest net (direct + indirect) impact in inhibiting platelet-thrombus formation and preventing ACS events. A cross-sectional, case-control study will be conducted to compare 5-NT-mediated platelet reactivity and thrombosis between depressed and non-depressed patients with coronary artery disease (CAD) history. The direct in vitro effects of the SSRIs and 5-HT2A receptor antagonists will also be assessed. A randomized, 3 active arm, 1 control arm, depression intervention trial will be conducted to compare the in vivo net effects of pharmacologic (the SSRIs and 5-HT2A receptor antagonists) treatment and the indirect effects of a non-pharmacologic (cognitive behavioral therapy) treatment on platelet reactivity and thrombosis in depressed CAD patients. By defining differences in direct-platelet, CNS-mediated indirect, and net effects on platelet reactivity and thrombus formation, depression interventions that are best at inhibiting platelet reactivity and thrombogenicity can then be tested for reducing cardiovascular morbidity and mortality.